The premise behind this grant application if that characterization and understanding of the pharmacology of an antineoplastic agent should allow better utilization of that agent in the clinical arena. Impeccable characterization of the clinical toxicities and maximum tolerated dose of an agent is no longer sufficient. Pharmacologic characteristics of an agent that ideally would be developed in its initial clinical trials include: pharmacokinetics, metabolism and pharmacodynamic manifestations on molecular and cellular, as well as, clinical levels. With this abiding philosophy and hypothesis, it is our intent to provide scientifically directed Phase I trials of promising anti-cancer agents available through the National Cancer Institute. The agents may come from the NCI's drug screening program, or may be referred to the NCI from outside sources. In pursuit of this specific aim, we intend to apply principles well established at our institution regarding integration of drug metabolism, pharmacokinetics, and pharmacokinetic/pharmacodynamic relationships into clinical trial designs. Furthermore, we intend to extend our activities integrating information regarding the mechanism of action into clinical trial design, and interpretation of the pharmaco-dynamic consequences of drug therapy. The specific goals of the application are: a) To define the acute toxicities of new anticancer agents in patients with advanced cancer; b) to re-define the acute toxicities and pharmacokinetics of existing anticancer agents administered in combination with colony stimulating factors and other toxicity-ameliorating agents, which may facilitate the exploration of more effective doses and schedules; c) to provide information on the pharmacologic characteristics (absorption, distribution, metabolism, and elimination) of selected antitumor agents; d) to define treatment regimens for evaluation of antitumor activity in Phase II trials; e) based on pharmacologic characteristics, to establish appropriate Phase II doses in special patient populations, such as those with impaired end-organ function or with heavy pretreatment, geriatric populations, and to explore pharmacokinetic and pharmacodynamic differences based on gender, race or ethnic group; f) to obtain preliminary information on pharmacokinetic/pharmacodynamic, correlations which can then be extended in Phase II trials; g) to incorporate ancillary basic laboratory studies, when possible and appropriate, to enhance our understanding of the biochemical and/or biological mechanisms of drug actions.